This is a Phase 1b, open-label, multicenter study designed to evaluate the safety and pharmacokinetics of venetoclax as a single-agent and in combination with azacitidine in participants with relapsed/refractory Myelodysplastic Syndromes (MDS).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
Tablet
Powder for injection, subcutaneously or intravenous
AUCt for azacitidine
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine
Time frame: Up to 32 days
Clearance (CL) for azacitidine
Time frame: Up to 32 days
Cmax for azacitidine
Maximum plasma concentration (Cmax) of azacitidine
Time frame: Up to 32 days
Tmax for venetoclax
Time to Cmax (peak time, Tmax) for venetoclax
Time frame: Up to 32 days
Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine
Time frame: Measured from Day 1 until day 28 per dose level.
AUC[0 to infinity] for azacitidine
Area under the plasma concentration-time curve from Time 0 to infinite time.
Time frame: Up to 32 days
Tmax for azacitidine
Time to Cmax (peak time, Tmax) for azacitidine
Time frame: Up to 32 days
AUC [0-24] for venetoclax
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax
Time frame: Up to 32 days
AUCt for venetoclax
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax
Time frame: Up to 32 days
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University of Arizona Cancer Center - North Campus /ID# 157503
Tucson, Arizona, United States
University of Colorado Hospital /ID# 155365
Aurora, Colorado, United States
Yale University /ID# 162544
New Haven, Connecticut, United States
Duplicate_University of Chicago /ID# 155364
Chicago, Illinois, United States
Pediatric Endocrine Associates /ID# 171227
Boston, Massachusetts, United States
Dana-Farber Cancer Institute /ID# 155361
Boston, Massachusetts, United States
University of Massachusetts - Worcester /ID# 155366
Worcester, Massachusetts, United States
Columbia Univ Medical Center /ID# 156388
New York, New York, United States
Oregon Health and Science University /ID# 155360
Portland, Oregon, United States
University of Texas MD Anderson Cancer Center /ID# 155362
Houston, Texas, United States
...and 13 more locations
Cmax of venetoclax
Maximum plasma concentration (Cmax) of venetoclax
Time frame: Up to 32 days
Half-life (t[1/2]) for azacitidine
Terminal elimination half-life (t\[1/2\]) for azacitidine
Time frame: Up to 32 days
Number of Participants With Adverse Events (AEs)
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
Time frame: Up to Maximum of 24 months
Event-Free Survival (EFS)
Time frame: Measured from the date of the first dose of study drug to date of earliest disease progression, death, or initiation of new non-protocol-specified anti-MDS therapy without documented progression, and for up to 5 years after the last subject is enrolled.
Overall Survival (OS)
Time frame: Measured from the date of first dose of study drug to the date of death, and for up to 5 years after the last subject is enrolled.
Rate of Modified Overall Response (mORR)
Proportion of participants with a mORR using best outcome will be calculated.
Time frame: Measured from Cycle 1 Day 1 (C1D1) as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Time to next treatment (TTNT)
Time frame: Measured from first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last subject is enrolled.
Duration of mORR
Defined as the number of days from the date of first response (CR, mCR or PR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier..
Time frame: Measured from the date of first response (CR, mCR or PR) to the earliest documentation of progressive disease (PD), and for an anticipated maximum duration of 24 months.
Rate of platelet (PLT) transfusion independence
Proportion of participants who become platelet transfusion-independent
Time frame: Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Time to Transformation acute myeloid leukemia (AML)
Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.
Time frame: Measured from the date of first dose of study drug to the date of documented AML transformation for an anticipated maximum duration of 24 months.
Progression-Free Survival (PFS)
Time frame: Measured from the date of the first dose of study drug to the date of earliest disease progression or death, and for an anticipated maximum duration of 24 months.
Overall Response Rate (ORR)
ORR (equals the sum of rates of complete remission \[CR\] + marrow complete remission (mCR) + partial remission \[PR\]) of venetoclax as a single-agent and in combination with azacitidine.
Time frame: Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Complete Remission (CR) Rate
Proportion of subjects who achieved a complete remission.
Time frame: Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Rate of red blood cell (RBC) transfusion independence
Proportion of red blood cell (RBC) transfusion independence.
Time frame: Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Duration of Complete Response (CR)
Duration of CR will be defined as the number of days from the date of first response CR to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.
Time frame: Measured from date of first response (CR) to the to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.
Rate of Hematologic Improvement (HI)
Proportion of participants with HI (erythroid/platelet/neutrophil responses)
Time frame: Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Rate of marrow complete remission (mCR)
Proportion of participants with marrow complete remission with or without hematological improvement.
Time frame: Measured from Cycle 1 Day 1 (C1D1) as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Duration of ORR
Duration of response (ORR) will be defined as the number of days from the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.
Time frame: Measured from the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.